This project includes analytic and methodologic studies aimed at elucidating the etiopathogenesis of prostate cancer. Our efforts relate to a variety of environmental, genetic, and hormonal predictors of prostate cancer risk in special populations. We have conducted a multidisciplinary study in China to assess risk factors for prostate cancer in a low-risk population in order to understand more clearly the reasons for the large racial differences in prostate cancer risk. That study involved the collection of multiple biologic samples, with a primary aim of assessing risk factors and how westernization influences the risk of prostate cancer. The study also involved the collection of tissue samples from prostate cancer tumors to permit precise tumor classification as well as assays of tumor biomarkers, in some cases using newly developed tissue microarray techniques. In addition to specific dietary factors, dietary patterns will be identified and compared with those of controls to evaluate whether a western-style diet in China is related to excess prostate cancer risk. The study is also assessing biological correlates of westernization to look for potential biological links between westernization and excess prostate cancer risk. Data on genotypes and circulating levels of hormones provide a unique opportunity to investigate the interrelationships between serum hormones and genetic variants to gain insights into the functional significance of these genetic markers. In another study of prostate cancer in 15 cities in China, we are assessing the role of soy in prostate cancer by developing a dietary isoflavone index. In Ghana, Africa, we have conducted a population-based survey of men to assess the population prevalence of prostatic disease. We have also collected consented into the study a clinical series of men diagnosed with prostate cancer. This dynamic epidemiologic design of a population survey combined with a larger case series, is enabling us to assess the burden of prostate cancer in African men as well as assess risk factors associated with prostate cancer in an important and understudied population. Biological samples collected from the 1,038 healthy men in the population survey component will allow us to establish the nutritional, hormonal, and genetic profiles of African men. In addition, linking interview data from these 1, 038 healthy subjects with biomarkers will produce insights into whether westernization in African men is associated with an adverse metabolic profile (obesity; abdominal obesity; higher levels of insulin, low-density lipoprotein, and insulin-like growth factor I), which has been associated with excess prostate cancer risk. The additional 677 prostate cancer cases that we recruited through the clinical component has enabled us to conduct a genome wide association study (GWAS) of prostate cancer in this unique population. In addition, we have sequenced the 8q24 region and identified several novel variants. In addition, several nested case-control studies in large cohorts, including Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and the Prostate Cancer Prevention Trial (PCPT), and the American Cancer Society Nutrition Cohort (CPS-II), we are assessing the relationships of obesity, dietary patterns, insulin resistance, and chronic inflammation with subsequent risk of prostate cancer. Together, these cohorts provide over 3,000 prostate cancer cases for the investigation of prostate cancer etiology. They are unique in having collected pre-morbid blood and multiple biologic samples over time, permitting an assessment of how hormone and other biomarker levels change as patients approach diagnosis. A methodologic study is currently underway to evaluate whether circulating levels of androgens reflect intraprostatic androgenicity, a key issue in hormonal carcinogenesis of the prostate. This methodologic study will collect samples of fasting blood and snap-frozen fresh tissue(over 3,000 pieces) from 600 study subjects in three racial/ethnic groups. Data from this study will provide a unique opportunity to investigate the interrelationships among serum and tissue hormones and variants in genes involved in the androgen metabolism pathways to provide critical data for determining the functional significance of these genetic markers. The collection of tissue samples also will provide a unique opportunity for gene expression studies.